cancers Review Prospects for Using Expression Patterns of Paramyxovirus Receptors as Biomarkers for Oncolytic Virotherapy Olga V. Matveeva 1,* and Svetlana A. Shabalina 2,* 1 Sendai Viralytics LLC, 23 Nylander Way, Acton, MA 01720, USA 2 National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA * Correspondence: [email protected] (O.V.M.); [email protected] (S.A.S.) Received: 27 October 2020; Accepted: 1 December 2020; Published: 5 December 2020 Simple Summary: Some non-pathogenic viruses that do not cause serious illness in humans can efficiently target and kill cancer cells and may be considered candidates for cancer treatment with virotherapy. However, many cancer cells are protected from viruses. An important goal of personalized cancer treatment is to identify viruses that can kill a certain type of cancer cells. To this end, researchers investigate expression patterns of cell entry receptors, which viruses use to bind to and enter host cells. We summarized and analyzed the receptor expression patterns of two paramyxoviruses: The non-pathogenic measles and the Sendai viruses. The receptors for these viruses are different and can be proteins or lipids with attached carbohydrates. This review discusses the prospects for using these paramyxovirus receptors as biomarkers for successful personalized virotherapy for certain types of cancer. Abstract: The effectiveness of oncolytic virotherapy in cancer treatment depends on several factors, including successful virus delivery to the tumor, ability of the virus to enter the target malignant cell, virus replication, and the release of progeny virions from infected cells. The multi-stage process is influenced by the efficiency with which the virus enters host cells via specific receptors. This review describes natural and artificial receptors for two oncolytic paramyxoviruses, nonpathogenic measles, and Sendai viruses. Cell entry receptors are proteins for measles virus (MV) and sialylated glycans (sialylated glycoproteins or glycolipids/gangliosides) for Sendai virus (SeV). Accumulated published data reviewed here show different levels of expression of cell surface receptors for both viruses in different malignancies. Patients whose tumor cells have low or no expression of receptors for a specific oncolytic virus cannot be successfully treated with the virus. Recent published studies have revealed that an expression signature for immune genes is another important factor that determines the vulnerability of tumor cells to viral infection. In the future, a combination of expression signatures of immune and receptor genes could be used to find a set of oncolytic viruses that are more effective for specific malignancies. Keywords: oncolytic viruses; oncolytic virotherapy; viral oncolysis; measles virus; Sendai virus; biomarkers; virus receptors; receptor retargeting; virus receptor expression; protein receptors; glycosphingolipid receptors; gangliosides 1. Introduction Oncolytic viruses are promising new agents for cancer treatment. They can kill cancer cells directly through infection or indirectly through activation of the immune system [1,2]. For the most effective Cancers 2020, 12, 3659; doi:10.3390/cancers12123659 www.mdpi.com/journal/cancers Cancers 2020, 12, 3659 2 of 28 virotherapy, elimination of malignant cells with a combination of both direct and indirect destruction is desirable. Like all viruses, oncolytic viruses use specific receptors to bind to and enter host cells. This review describes the tendency of tumor cells to overexpress certain viral receptors, but it also Cancers 2020, 12, x 2 of 27 shows that, to varying degrees, these receptors are also expressed in many normal cells. However, regardlessdestruction of whether is desirable. cells areLike normal all viruses, or malignant, oncolytic viruses absence use of specific receptors receptors for a to particular bind to and virus enter makes the cellshost resistantcells. This to review this virus describes infection. the tendency So, for of better tumor identification cells to overexpress of individual certain viral patients receptors, who are mostbut likely it also tobenefit shows that from, to virotherapy, varying degrees, their these tumor receptors cells should are also be expressed screened in for many the presencenormal cells. of virus receptors.However, For manyregardless oncolytic of whether viruses, cells suchare normal receptors or malignant, are well characterized.absence of receptors Thus, for simple a particular tests that evaluatevirus protein makes the or RNAcells resistant levels in to tumor this virus tissue infection. could So, provide for better information identification about of individual expression patients levels of a who are most likely to benefit from virotherapy, their tumor cells should be screened for the presence virus receptor. of virus receptors. For many oncolytic viruses, such receptors are well characterized. Thus, simple Receptor mediated virus entry into a cell is only the first step in viral infection. Next, the virus tests that evaluate protein or RNA levels in tumor tissue could provide information about expression mustlevels break of through a virus receptor. the cellular antiviral defense system, which usually effectively protects normal cells fromReceptor any virus mediated infection. virus Key entry players into a cell in such is only protection the first step are in interferons viral infection. (IFNs); Next they, the helpvirus cells detectmust the presencebreak through of a virusthe cellular and, inantiviral response, defense restrict system proliferation,, which usually slow effectively down metabolic protects normal processes, and triggercells from apoptosis any virus [3 infection.,4]. However, Key players malignant in such cells protection frequently are interferons have dysfunctional (IFNs); they IFN help pathways. cells Suchdetect dysfunction the presence helps of them a virus to evadeand, in theresponse, immune restrict system proliferation, and survive, slow thus down promoting metabolic tumorprocesses growth., The sameand t IFNrigger defects apoptosis that [3,4] help. However, cancer cells malignant escape immunecells frequently surveillance have dysfunctional make them vulnerableIFN pathways to. virus infectionSuch [ 5dysfunction]. Nevertheless, helps not them all malignantto evade the cells immune have dysfunctionalsystem and survive IFN pathways., thus promot Someing oftumor them can growth. The same IFN defects that help cancer cells escape immune surveillance make them produce and/or respond to IFN signals and protect themselves from a virus infection. So, theoretically, vulnerable to virus infection [5]. Nevertheless, not all malignant cells have dysfunctional IFN evenpathways. if a cancer Some cell hadof them receptors can produce for a particular and/or respond oncolytic to IFN virus signals it still and could protect be themselves resistant tofrom infection a by thevirus virus. infection. So, theoretically, even if a cancer cell had receptors for a particular oncolytic virus it Somestill could viruses be resistant require to cells infection to express by the processing virus. enzymes that modify or cleave the viral proteins necessaryS forome the viruses formation require ofcells mature to express infectious processing virions. enzymes Thus, that modif fusiony or protein cleave inthe paramyxoviruses viral proteins is synthesizednecessary for as anthe inactiveformation precursor of mature andinfectiou is activateds virions. throughThus, fusion proteolytic protein in cleavage paramyxoviruses by the cellular is protease.synthesized Without as such an inactive cleavage precursor the virus and isunable is activated to sustain through infection. proteolytic For MV,cleavage this activatingby the cellular protease is furinprotease. [6] and Without for SeV such it cancleavage be a numberthe virus ofis serineunable proteasesto sustain (TPSB2infection [. 7For–9], MV PRSS1, this [activating10], PLG [11], F10 [12prote], andase is TMPRSS2 furin [6] and [13 for]). SeV Some it can of be these a number proteases of serine are proteases overexpressed (TPSB2 [7– in9],cancer PRSS1 [10] cells, PLG [14 –16]. [11], F10 [12], and TMPRSS2 [13]). Some of these proteases are overexpressed in cancer cells [14–16]. In addition to those listed, the expression levels of other host genes influence vulnerability of cancer In addition to those listed, the expression levels of other host genes influence vulnerability of cancer cellscells to a virusto a virus infection. infection. Figure Figure1 illustrates1 illustrates factors factors necessarynecessary for for a acell cell to to become become vulnerable vulnerable to to paramyxovirusparamyxovirus infection. infection. FigureFigure 1. Factors 1. Factors influencing influencing cells’ cells’vulnerability vulnerability to to paramyxovirus paramyxovirus infection. infection. The host The cell host needs cell to needs (1) to (1) expressexpress virus virus receptors receptors (2)(2) havehave a malfunctioning malfunctioning IFN IFN pathway, pathway, (3) (3) express express proteases proteases responsible responsible for for proteolyticproteolytic activation activation of virus of fusionvirus fusion rotein, rotein and (4), and have (4) other have genes other that genes require that further require identification. further identification. Cancers 2020, 12, 3659 3 of 28 Cancers 2020, 12, x 3 of 27 To predict if a patient is likely to respond to oncolytic virotherapy, testing for